This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge topic, 03-MH-101*: Biomarkers in mental disorders. Psychiatric Disorders such as alcohol and other substance abuse disorders, unipolar depression, bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) are amongst the most significant causes of morbidity and mortality in the USA. Although treatments for these disorders are available they are less than adequate. Prevention strategies for these disorders are key to any future reduction in morbidity and mortality. Abnormal function in reward systems is associated with these major psychiatric disorders. An increasingly large body of research supports the role of two central brain regions, the ventral and dorsal striatal regions, in reward processing, particularly the ventral striatal (VS) region. Increasing evidence from animal studies and human neuroimaging studies involving pharmacological challenge with amphetamine and methylphenidate support the role of dopamine (DA) release in reward-related ventral striatal (VS) functioning. Better understanding of abnormalities in neurotransmitter function associated with functional abnormalities in reward systems observed in these psychiatric disorders is a vital step forward in the development of strategies to identify those at risk who may best benefit from primary preventative interventions. Furthermore, such understanding will inform the development of new treatments that target alterations in reward systems in these different psychiatric disorders. The essential initial step in these developments is the characterization of the relationship between the neural substrates of reward processing and dopaminergic function in healthy young individuals in early adulthood, a critical developmental period, during which risk for the above psychiatric disorders increases. To do this, we aim to use functional magnetic resonance imaging (fMRI) and [11C]raclopride Positron Emission Tomography (PET) during a physiological challenge (monetary reward task) and a pharmacological challenge, (d-amphetamine) in healthy adults (N =24, 12 females/12 males). From this work we will develop a pharmacologically informed fMRI probe that can then be utilized in future studies in patient populations and youth at high risk. We have three main aims and hypotheses. 1. We want to assess the relationship between the magnitude of VS activity (measured as the regional change, in BOLD fMRI signal) and DA release (measured as the change in [11C]raclopride binding, abbreviated to BPND) during a monetary reward task. Our hypotheses is that in healthy individuals greater magnitude of VS BOLD signal change will be associated with greater VS DA release (measured as greater displacement of the radiotracer [11C]raclopride) during the same monetary reward task. 2. Our second aim is to assess the relationship between magnitude of VS activity (measured as the change in BOLD fMRI signal) during a monetary reward task and amphetamine-induced VS DA release (measured as the change in [11C]raclopride BPND following oral amphetamine 0.5 mg/kg). Our hypothesis for this second aim is that in healthy individuals greater magnitude of VS BOLD signal change during the monetary reward task will be associated with greater amphetamine-induced DA release. Our third aim is to examine the relationship of impulsivity and change in VS BOLD signal with physiological and pharmacological change in [11C]raclopride BPND as first stage toward understanding how abnormal VS DA transmission may be associated with impulsive behaviors associated with the above psychiatric disorders. Our hypothesis is that in healthy volunteers there will be a positive relationship between the magnitude of VS BOLD signal change during the monetary reward task and impulsivity. We will explore the relationship between these measures and VS physiological and amphetamine-induced DA release. In further exploratory analyses we will assess the relationship between the magnitude of task-induced VS DA release and amphetamine-induced VS DA release hypothesizing that they will be highly correlated. The findings of the proposed study have implications for understanding the pathophysiology and treatment of psychiatric disorders that involve the disruption of neural reward circuits and will have a number of potential impacts.These center around an understanding of the pathophysiology of these disorders, the development of usable biomarkers for the identification of those most at risk of the development of disorder which will allow appropriately targeted primary prevention and finally, the development of pathophysiologically based treatments. In addition, the multi-modal approach in this study will validate the use of fMRI alone in young high risk populations unable to undergo PET studies involving radiation and pharmacological challenges. The techniques developed and validated in the proposed study will therefore pave the way for future studies of dopamine system functioning in clinical and high-risk populations utilizing fMRI alone. By identifying pathophysiologically based fMRI biomarkers and allowing primary prevention, these future studies will potentially have a major impact on the prevalence and outcome of alcohol and substance use disorders, unipolar depression, bipolar disorder, and impulsivity-related disorders such as ADHD, which currently together affect at least 17% of the US population in any 12-month period and comprise some of the leading causes of lost disability-adjusted life years. PUBLIC HEALTH RELEVANCE: Psychiatric disorders such as alcoholism, drug dependence, depression, bipolar disorder and attention deficit disorder affect almost a fifth of Americans every year and are also some of the top causes of lost working years. We will combine functional Magnetic resonance imaging, (fMRI), which shows how the brain activates, and positron emission tomography, which shows how much the brain chemical dopamine is released during the activations. Understanding more about how the brain works like this will allow us to do studies using just fMRI that will identify people most at risk for these disorders before they get sick, hopefully allow us to stop them from getting sick and develop better treatments for those already sick.